Tyrosine kinases control cell proliferation, differentiation, migration and survival, and are often deregulated in cancer. We are investigating Src proto-oncogene dependent cell migrations during mammalian development. Our past results showed that a Src-dependent signaling mechanism regulates the precise positioning and layering of cells in the developing mouse brain. Our more recent results provide evidence for a Src signaling event that increases membrane-localized N-cadherin on randomly-moving multipolar neurons in the neocortex. N-cadherin then enables directional cell migration. We also discovered the importance of tyrosine phosphorylation-dependent protein turnover in terminating neuron migrations in the cortex, and extended this finding to show that a similar process inhibits Src-dependent tumorigenesis. Therefore we propose to investigate three innovative hypotheses: (1) That a secreted signaling molecule, Reelin, increases surface N- cadherin levels by altering traffic (endo-/exocytosis) or inducing stabilization of surface N-cadherin. (2) That multipolar cells interpret direction signals from the environment through N-cadherin itself or through a cadherin- associated co-receptor. The direction signal may be conveyed by cell-cell contact or by a diffusible signal. (3) That the final positions of cortical neurons are determined by the timely cessation of Reelin-dependent terminal translocation, which stops when Cullin5-dependent mechanisms destroy the Src substrate, Dab1. Progress in these Aims will reveal molecular mechanisms underlying complex cell migrations in vivo.